Animal experiments have suggested that muscle glycogen depletion following exercise is associated with increased insulin sensitivity compared to glycogen replete muscles. This study was designed to see if this is also true in man. After 4 days of rest, twenty males had a muscle biopsy followed by a euglycemic clamp at plasma insulin concentrations of 100 and 1900 MuU/ml, with simultaneous indirect calorimetry. This was repeated one week later but after glycogen depleting exercise the night before. There were significant decreases in muscle glycogen content and significant increases in muscle glycogen synthase activity. The basal and insulin stimulated carbohydrate oxidation rates were decreased and the carbohydrate storage rates were increased. There were variable changes in the total glucose disposal rate. The changes in the carbohydrate storage rate and in the total glucose disposal rate were well correlated with changes in the muscle glycogen synthase activity. The results suggest that muscle glycogen synthase activity may be rate limiting for carbohydrate storage rates and therefore for total glucose disposal rates in glycogen depleted men.